Genetic Variation and Its Implications

### Genetic Variation

• Human genomes are 99.9% identical, showcasing 0.1% variation
• Human reproduction through sexual means introduces genetic differences, crucial for evolution
• Genetic variation enables adaptation to environmental changes and safeguards against disease extinction

Large-Scale Genetic Variations

• Aneuploidy: One or more chromosomes are missing or present in extra copies. Examples: Trisomy 21 (Down syndrome), Trisomy 13 (Patau syndrome), Trisomy 18 (Edwards syndrome), XXY (Klinefelter syndrome), X (Turner syndrome).
• Translocations/Transversions: Exchange of DNA segments between two different chromosomes during meiosis. Incidence: 1 in 500 newborns.
• Copy Number Variants (CNVs): Large sections of DNA (over 1000 base pairs) are duplicated or deleted. Incidence: All humans possess multiple CNVs.

Small-Scale Genetic Variations

• Single Nucleotide Polymorphisms (SNPs): Single base-pair differences in DNA sequence. Incidence: We possess approximately 3.5 million SNPs.
• Microsatellites: Short (2-5 base pairs) repeating units in DNA sequence. Incidence: All humans have ~10,000 microsatellites in their genomes.
• Insertions and Deletions: Short sections of DNA (one or a few base pairs) that are present in some individuals but not others. Incidence: All humans have ~20,000 insertions and deletions.

Pathogenic Mutations

• Majority of mutations occur outside genes, not causing disease.
• Pathogenic mutations alter gene function negatively, causing diverse effects:
  • Gene Knockout or Copy Number Increase: Through CNVs.
  • Gene Rearrangment: Through transversions/translocations.
  • Amino Acid Sequence Change: Non-synonymous mutation.
  • Premature Stop Codon Insertion: Non-sense mutation.
  • Splice-Site Mutation: Alters gene splicing.

Cancer Cell Genetic Variation

• Cancer cells exhibit genomic instability, characterized by rapid genetic changes.
• "Driver" mutations contribute to cancer development through:
  • Sustaining genomic instability.
  • Bypassing safety mechanisms.
  • Enabling rapid cell growth and division.
  • Facilitating metastasis.
• Genomic instability in cancer cells leads to:
  • Large-scale deletions and amplifications.
  • Chromosomal rearrangements.
  • Epigenetic changes.
• Understanding genetic variation in cancer cells is crucial for:
  • Targeted cancer therapies based on specific gene mutations.
  • Personalized medicine approaches for cancer treatment.

Large Scale Genetic Variation

• Aneuploidy: One or more chromosomes are either duplicated or missing. Example: Trisomy 21 (Down syndrome).

  • Occurs in approximately 1 in 1000 newborns.
  • Often results in significant changes in gene expression, leading to developmental delays and other clinical issues.
  • Other examples: Trisomy 13 (Patau Syndrome), Trisomy 18 (Edwards Syndrome), XXY (Klinefelters), and Monosomy X (Turner).

• Translocations/Transversions: Exchange of DNA segments between two different chromosomes during meiosis.

  • Occurs in approximately 1 in 500 newborns.
  • Clinical implications depend on the specifics of the exchange:
    • Net gain or loss of DNA.
    • Disruption of gene sequence.
    • Impact on gametogenesis.

• Copy Number Variants (CNVs): Large sections of DNA (over 1000 base pairs) that are duplicated or deleted.

  • Found in every individual.
  • Most are benign; however, larger CNVs (over 1 million base pairs) can lead to developmental delays, autism, epilepsy, etc.

Small Scale Genetic Variation

• Microsatellites: Short, repeated DNA units (2-5 base pairs) that vary in number between individuals.

  • Found in all genomes, typically around 10,000 per individual.
  • Rarely cause disease.

• Single Nucleotide Polymorphisms (SNPs): Single base-pair differences in DNA sequences.

  • Found in all genomes, typically around 3.5 million per individual.
  • Generally benign or have a small effect on disease, but can be strongly disease-causing in rare cases.

• Insertions/Deletions: Small sections of DNA (one or a few pairs) present in some individuals but not others.

  • Found in all genomes, typically around 20,000 per individual.
  • Rarely cause disease but can be damaging if they occur in exons.

Pathogenic Mutations

• Pathogenic mutations disrupt gene function and can lead to disease.

• Large-scale pathogenic mutations (e.g., aneuploidy, translocations, CNVs) cause:

  • Large-scale changes in gene expression, affecting multiple genes.

• Small-scale pathogenic mutations cause:

  • Changes in amino acid sequences.
  • Aberrant splicing (skipping or introduction of an exon).
  • Premature translation stop.

• Example: CFTR delta-508 mutation: Deletion of a single amino acid (phenylalanine) in the CFTR gene. This prevents the protein from being processed properly, leading to cystic fibrosis.

Genetic Variation in Malignant Cells

• Cancer is characterized by genomic instability. This means there are many genetic changes in cancer cells.
• Genetic changes can both cause and be caused by cancer.
• Genomic instability allows cancer cells to:
  • Bypass safety mechanisms.
  • Grow and divide rapidly.
  • Metastasize.
• Genomic instability in cancer cells leads to:
  • Large-scale deletions and amplifications.
  • Chromosomal rearrangements
  • Epigenetic changes.
• Cancer is not a single disease:
  • Different cancers occur in different tissues.
  • Within a single cancer, different cell clones can exist.
  • The specific genes affected (BCR-Abl, HER2, etc.) can vary from one cancer to the next.
  • Tumor profiling is a growing field that analyzes specific genes and mutations to personalize cancer treatment.

Large-scale Genetic Variation

• Aneuploidy: One or more chromosomes are present in an extra copy or missing.
  • Example: Trisomy 21 (Down Syndrome)
  • Incidence: Rare (approximately 1 in 1000 newborns)
  • Clinical Relevance: Usually causes significant changes in gene expression with associated clinical consequences (e.g., learning disability, developmental delays).
  • Other viable trisomies include trisomy 13 (Patau Syndrome), trisomy 18 (Edwards Syndrome), and XXY ( Klinefelter's syndrome).
  • Viable monosomy (X - Turner)
• Translocations/Transversions: Exchange of DNA during meiosis between two different chromosomes.
  • Incidence: Approximately 1 in 500 newborns.
  • Clinical Relevance: Depends on the event.
    • Is there net gain or loss of DNA?
    • Is there disruption of gene sequence?
    • Do issues arise in gametogenesis-meiosis?
• Copy Number Variants (CNVs): Deletions or duplications of DNA greater than 1000 base pairs in size. They can be several million bases in size.
  • Incidence: Everyone carries multiple copy number variants in their genome.
  • Clinical Relevance: Most CNVs are benign, but larger ones (>1 million base pairs) tend to be pathogenic (learning disability, autism, epilepsy, etc.).

Small-scale Genetic Variation

• Microsatellites: Short (2-5bp) repeat units in DNA sequence.
  • The number of copies varies from individual to individual.
  • Incidence: Common. Everyone carries approximately 10,000 microsatellites in their genome.
  • Clinical Relevance: Rarely disease-causing; the vast majority are benign.
• Single Nucleotide Polymorphisms (SNPs): A single base-pair change in the DNA sequence.
  • Incidence: Everyone carries around 3.5 million SNPs.
  • Clinical Relevance: Similar to microsatellite variation, the vast majority are benign or have a very small effect on disease. However, in rare cases, they can be strong and disease-causing.
• Insertions & Deletions: Small sections of DNA (one or limited number of base-pairs) present in some individuals but not in others.
  • Incidence: Common. Everyone carries approximately 20,000 in their genome.
  • Clinical Relevance: Rarely disease-causing; the vast majority are benign. Can be damaging if they occur in exons.

Pathogenic Mutations

• The vast majority of mutations occur outside of genes (98% of the genome is not genic), and most mutations do not cause disease.
• Pathogenic mutations alter gene function deleteriously.
  • They can:
    • Knockout or increase the copy number of a gene
    • Rearrange multiple genes
    • Change the amino acid sequence
    • Lead to premature stop of translation
    • Alter splicing

The Features of Large-scale Pathogenic Mutations

• Large-scale pathogenic variations (ploidy, translocations, CNVs, etc.) result in:
  • Gross changes in gene expression: Protein levels from multiple different genes are altered.

The Features of Small-scale Pathogenic Mutations

• Small-scale pathogenic variation results in:
  • Changing the amino acid sequence.
  • Skipping or introduction of an exon (aberrant splicing).
  • Premature stop to translation.

The Nature and Extent of Genetic Variation in Malignant Cells

• Cancer is characterized by "genomic instability."
• Genetic changes lead to cancer, and cancer causes genetic changes.
• Genomic instability in cancer cells rapidly "evolves" critical "driver" mutations that allow:
  • Genomic instability to persist.
  • Safety mechanisms to be bypassed.
  • Rapid growth and division of cells.
  • Metastasis.

The Nature and Extent of Genetic Variation in Malignant Cells

• Genomic instability in cancer cells leads to:
  • Large-scale deletions and amplifications.
  • Chromosomal rearrangements.
  • Epigenetic changes.

Cancer & Genetics

• Different cancers arise from different tissues.
• Within a cancer, different "clones" of cells often exist.
• Some clones may be sensitive to one pharmacological agent but not to another.
• Genetic characterization of cancers is a growing field:
  • Specific genes (BCR-Abl, HER2, etc.)
  • Tumor profiling.